Title:A Systems Biology Road Map for the Discovery of Drugs Targeting Cancer Cell Metabolism
Volume: 20
Issue: 15
Author(s): Lilia Alberghina, Daniela Gaglio, Rosa Maria Moresco, Maria Carla Gilardi, Cristina Messa and Marco Vanoni
Affiliation:
Keywords:
Model, metabolic rewiring, glutamine, Warburg effect.
Abstract: Despite their different histological and molecular properties, different types of cancers share few essential functional alterations.
Some of these cancer hallmarks may easily be studied in in vitro cultures, while others are related to the way in which tumors grow
in vivo.
According to the systems biology paradigm, complex cellular functions arise as system-level properties from the dynamic interaction of a
large number of biomolecules. We previously newly defined four basic cancer cell properties derived from known cancer hallmarks amenable
to system-level investigation in cell cultures: enhanced growth, altered response to apoptotic cues, genomic instability and inability
to enter senescence following oncogenic signaling.
Here we summarize the major properties of enhanced growth that is dependent on metabolism rewiring - in which glucose is mostly used
by fermentation while glutamine provides nitrogen and carbon atoms for biosyntheses – and controlled by oncogene signaling. We then
briefly review the major drugs used to target signaling pathways in preclinical and clinical studies, whose clinical efficacy is unfortunately
severely limited by tumor resistance, substantially due to signaling cross-talk.
We present a systems biology roadmap that integrates different types of mathematical models with conventional and post-genomic biomolecular
analyses that will provide a deeper mechanistic understanding of the links between metabolism and uncontrolled cancer cell
growth. This approach is taken to be instrumental both in unraveling cancer’s first principles and in designing novel drugs able to target
one or more control or execution steps of the cancer rewired metabolism, in order to achieve permanent arrest of tumor development.
